2-(2-Halophen oxy)acetamidines as antidepressants

ABSTRACT

A method useful for alleviating central nervous system depression comprises administration to animals of an effective amount of a 2-(2-halophenoxy) acetamidine. Compositions useful in practicing the method are also disclosed.

United States Patent [1 1 Abdallah et al.

[ Dec. 30, 1975 [54] 2-(2-HALOPHEN OXY)ACETAMIDINES AS ANTIDEPRESSANTS [7 5] lnventors: Abdulmuniem H. Abdallah; Philip J.

Shea, both of Midland, Mich.

[73] Assignee: The Dow Chemical Company,

Midland, Mich.

[22] Filed: Nov. 6, 1974 [21] Appl. No.: 521,436

[52] US. Cl. 424/326 [51] Int. Cl. A61K 31/155 [58] Field of Search..... 424/326; 260/564 R, 501.14

[56] References Cited UNITED STATES PATENTS 3,139,455 6/1964 Campbell 424/326 3,445,517 5/1969 Mills 424/326 OTHER PUBLICATIONS Chem. Abst. 44 8397 (1950).

Primary ExaminerStanley .1. Friedman Attorney, Agent, or FirmMaynard R. Johnson [57] ABSTRACT 5 Claims, No Drawings Z-(Z-HALOPHEN OXY )ACETAMIDINES AS ANTIDEPRESSANTS BACKGROUND OF THE INVENTION Description of the Prior Art The halophenoxy amidine compounds of the invention can be prepared by a classical method, the Pinner amidine synthesis.

Chlorophenoxy acetamidines, including 2-(2-chloro ,phenoxy) acetamidine nitrate, are known compounds.

Cumming and Golombok, J. Roy. Tech. Coll. (Glasgow) 5, 70-9 (1950); Chemical Abstracts 44,8397.

A number of N-monosubstituted and unsubstituted amidines are known. Craver et al., J. Pharm. Exptl. Therap. 99, 353 (1950); Netherlands Application 6,508,754, CA. 65, 21810 (1966); U.S. Pat Nos. 3,344,138, 3,417,122 and 3,334,137. Chlorobenzamidines are disclosed by Markwardt et al., Pharmazie 1969 24 (7), 400-2, and European J. Biochem. 6; 5026(l968). Chlorophenoxy acetamidoximes with hypotensive activity are disclosed in U.S. Pat. No. 3,139,455.

SUMMARY OF THE INVENTION This invention is directed to a method which comprises administering to a mammal an effective antidepressant amount of 2-(2-halophenoxy) acetamidine compound or a pharmacologically-acceptable salt thereof, or a composition containing such substituted acetamidine compound or salt as the active antidepressant ingredient therein; said substituted halophenyl acetamidine compound corresponding to the formula:

wherein X represents halo. In the present specification and claims halo refers to chloro and bromo, the compound wherein X is halo being prepared.

It has been found that the 2-(2-halophenoxy) acetamidines of the above formula and their pharmacologically-acceptable salts have potent antidepressant properties. (For the purpose of brevity, such compounds will be hereinafter referred to as substituted amidines".) Administration of one or more of the substituted amidine compounds to mammals has been found to provide valuable antidepressant effects, providing for alleviation of central nervous system depression without accompanying central nervous stimulation or agitation. The compounds have exhibited little or no significant detrimental pharmacological effects at dosages consistent with good antidepressant activity. 2-(2- Chlorophenoxy) acetamidine hydrochloride has a particularly favorable ratio of oral toxicity (LD SO) to oral effective dose (ED 50).

The substituted amidine compounds are crystalline solids which are soluble in a variety of conventional liquids, including alcohols, chlorinated hydrocarbons, etc. In general, the pharmacologically-acceptable salts are more soluble in aqueous liquids than are the free base compounds, and the substituted amidines are preferably employed in the form of such salts.

As employed herein, the phrase pharmacologicallyacceptable salt refers to salts of the substituted amidines, the anions of which are relatively non-toxic and innocuous to mammals at dosages consistent with good activity so that side effects ascribable to the anions do not vitiate the beneficial effects of the substituted amidines. Suitable pharmacologically-acceptable salts which can be employed in the method and composition of the invention include those derived from mineral acids such as the hydrochloride, hydrobromide, phosphate, nitrate and sulfate salts, those derived from organic carboxylic acids such as the succinate, tartrate', citrate, malate, maleate, and acetate salts and those derived from organic sulfonic acids such as the methanesulfonate and toluene-sulfonate salts.

In practicing the method, one or more substituted amidine is administered internally to a mammal by a route effective to introduce an effective amount of the compound into the blood stream of the mammaLAdministration can be carried out either by a parenteral route such as by intravenous, intraperitoneal, subcutaneous or intramuscular injection, or by introduction into the gastrointestinal tract by oral administration, for example, to introduce the compound into the blood stream via the gastrointestinal tract. The substituted amidines are orally effective, and generally have a higher ratio of toxic dose to effective dose when orally administered, and this route is preferred. The effective amount of substituted amidine to be administered can also be referred to as an antidepressant amount (amount sufficient to alleviate central nervous system depression).

The antidepressant amount of compound, that is, the amount of the substituted amidine compound sufficient to provide the desired effect depends on various known factors such as the size, type, age and condition of the animal to be treated, the particular amidine or pharmacologically-acceptable salt employed, the route and frequency of administration, the type and degree of central nervous system condition involved, the time the compound is administered relative to prior and subsequent presentation of food and liquids, etc. In particular cases, the dosage to be administered can be ascertained by conventional range finding techniques, for example, by observing the effect produced at different dosage rates.

Generally, the compound is administered at dosage rates from about 1- to about 4 to about 25 to about 50 milligrams of substituted amidine compounds per kilogram of animal body weight. Higher dosage rates may be employed, for example, when the compound is administered orally in a timed release dosage form. When administered by injection, good results are obtained with an amount of from about I to about 25 milligrams of the amidine compound per kilogram of animal body weight. From about 1 to milligrams of the amidine compound per kilogram, depending on dosage unit form employed, provide good results when the compound is administered orally. In the case of mammals suffering from central nervous system depression (exhibiting symptoms of depression), administration of an antidepressant amount of the substituted amidine compound is preferably repeated at predetermined intervals. It is generally desirable to administer the individual dosages at the lowest antidepressant amount which provides the desired continuity consonant with a convenient dosing schedule. In a convenient repetitive procedure, the substituted amidines are administered in single or divided oral doses at daily rates of about 1 to 150 milligrams per kilogram per day.

In practicing the method of the invention, the active ingredient is preferably incorporated in a composition comprising a pharmaceutical carrier and from about 0.001 to about 95 percent by weight of the substituted amidine compound or a pharmacologically-acceptable salt thereof. The term pharmaceutical carrier refers to known pharmaceutical excipients useful in formulating pharmacologically-active compounds for internal administration to animals, and which are substantially non-toxic and non-sensitizing under conditions of use.

Suitable pharmaceutical carriers are known and disclosed in texts such as Remingtons Pharmaceutical Sciences, Thirteenth Ed., Martin (Ed.) Mack Publishing Co., Easton, Pa. (1965). The compositions can be prepared by known techniques for the preparation of tablets, capsules, lozenges, troches, elixirs, syrups, emulsions, dispersions, wettable and effervescent powders, sterile injectable compositions, and can contain suitable excipients known to be useful in the preparation of the particular type of composition desired.

Dosage units adaptable to oral administration such as tablets, capsules, lozenges, elixirs, syrups and the like are preferred and the active amidine compound can be formulated in conventional timed release capsule or tablet formulations.

Preferred compositions include sterile injectable solutions containing from about 0.001 to about percent by weight of the amidine compound in a pharmaceutical carrier suitable for injection, such as isotonic saline solution, Ringers Injection USP, and lactated Ringers USP, and the like. Preferred compositions for oral use include unit dosage forms such as capsules and compressed tablets, containing a pharmaceutical carrier and from about 1 to about 150 milligrams of amidine compound per unit.

The following examples are illustrative of the invention.

EXAMPLE 1 Separate groups of mice of the same origin and past history (5 mice per group) were administered 2-(2- chlorophenoxy) acetamidine hydrochloride in an aqueous carrier. Different groups were administered the compound by intraperitoneal injection at various dosage rates. Thirty minutes after the administration of the test compound, the mice were administered reserpine at a dosage rate of 2.5 milligrams per kilogram ofintraperitoneal injection. Separate groups of similar mice were similarly administered 2.5 milligrams of reserpine per kilogram 30 minutes after administration of various dosages of the known antidepressant. The mice were then observed for 45 minutes for symptoms of reserpine-induced depression.

In repeated prior check observations, the administration of 2.5 milligrams per kilogram (mg/kg) of reserpine intraperitoncally to mice has been observed to result in a classical progression of symptoms beginning with a characteristic dropping of the eyelids (ptosis) and later culminating in a generalized depression with decreased spontaneous motor activity and decreased responsiveness to auditory and tactile stimuli. Protection from reserpine-induced depression is indicated by the absence of the characteristic ptosis.

The results were employed to calculate the dose effective to protect 50 percent of the mice (ED by classical statistical procedures. The amidine compound 4 was found to have an ED of 2.3 mg/kg. In otheroperations the intraperitoneal acute 50 percent lethal dose (LD was found to be 150 mg/kg, the results corresponding to a Therapeutic Index A l? so EXAMPLE 2 The procedure of Example 1 was repeated, using oral administration of 2-(2-chlorophenoxy) acetamidine hydrochloride instead of intraperitoneal injection. The oral ED was found to be 1.6 mg/kg. The oral LD was found to be 422 mg/kg, and the Therapeutic Index 263.75.

In a similar operation carried out with rats as the test animals, the oral ED of the same compound was found to be 3.2 mg/kg.

EXAMPLE 3 In other operations with the test compound, 2-(4- chlorophenoxy) acetamidine hydrochloride, a number of other pharmacological evaluations are carried out.

The test compound is found to have no effect on pentylenetetrazole induced convulsions at i.p. dosages from 10 mg/kg up to 46.4 mg/kg and no effect on tryptamine induced convulsions in rats.

The test compound is found to potentiate symptoms of hyperexcitability, fighting and death induced by subcutaneous injection of 20 mg/kg of yohimbine hydrochloride in aggregated mice, with an ED of 8.8 mg/kg (i.p.) when administered 30 minutes prior to yohimbine challenge. Imipramine is found to have an ED of 0.7 mg/kg in this procedure. Lethality is used as the endpoint in calculating ED s in this procedure.

EXAMPLE 4 Solid dosage unit compositions with solid pharmaceutical carriers are made as follows:

25 Parts by weight of 2-(4-bromophenoxy)-acetamidine p-toluenesulfonate, parts by weight of starch USP, 25 parts of lactose and 0.75 part by weight magnesium stearate are intimately mixed together. The mixture is filled into No. 3 hard gelatin capsules, in the amount of milligrams per capsule. The resulting capsules, containing 25 milligrams of amidine compound per unit, are suitable for oral administration to animals.

5 Parts by weight of 2-(4-chlorophenoxy) acetamidine hydrochloride, 150 parts lactose, 15 parts starch, 18 parts talc and 0.2 parts stearic acid are mixed, compressed into slugs and screened to 14-16 mesh. The resulting granulation is compressed with a 19 millimeter punch and die to tablets weighing about milligrams. The tablets are adapted for oral administration.

What is claimed is:

l. A method useful for alleviating symptoms of central nervous system depression in animals comprising administering to an animal suffering from central nervous system depression an amount of a compound selected from the group consisting of a 2-(2-halophenoxy) acetamidine and a pharmacologicallyacceptable salt thereof effective to alleviate said symptoms.

6 administration to animals comprising from about 0.001 to about percent by weight of the amidine compound, and containing from about 1 to about milligrams of said compound per unit.

5. Method of claim 4 wherein the compound is 2-(2- chlorophenoxy) acetamidine hydrochloride. 

1. A METHOD USEFUL FOR ALLEVIATING SYMPTONS OF CENTRAL NERVOUS SYSTEM DEPRESSION IN ANIMALS COMPRISING ADMINISTERING TO AN ANIMAL SUFFERING FROM CENTRAL NERVOUS SYSTEM DEPRESSION AN AMOUNT OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A 2-(2-HALOPHENOXY) ACETAMIDINE AND A PHARMACOLOGICALLY-ACCEPTABLE SALT THEREOF EFFECTIVE TO ALLEVIATE SAID SYMPTONS.
 2. Method of claim 1 wherein the compound is selected from 2-(2-chlorophenoxy) acetamidine and its pharmacologically-acceptable salts.
 3. Method of claim 2 wherein the compound is 2-(2-chlorophenoxy) acetamidine hydrochloride.
 4. Method of claim 1 wherein the compound is administered in a dosage unit form adapted for internal administration to animals comprising from about 0.001 to about 95 percent by weight of the amidine compound, and containing from about 1 to about 150 milligrams of said compound per unit.
 5. Method of claim 4 wherein the compound is 2-(2-chlorophenoxy) acetamidine hydrochloride. 